Dibenzo(b,f)oxepin-and thiepin-10-yl compounds

ABSTRACT

New compounds having the following general formula:   IN WHICH X is =O, or =S; and R, and R1 are a variety of substitutents. The compounds have useful pharmacological activities which include hypertensive, sedative, muscle relaxant, local anesthetic, analgesic, anti-pyretic, and anti-inflammatory activities. Various salts of these compounds are also useful and are included within the scope of the present invention. Processes of preparing these compounds are described.

United States Patent [151 3,681,354

Mastursi et al. Aug. 1, 1972 i5 1 DlBENZO(B,F)0XEPIN-AND THIEPIN- OTHER PUBLICATIONS 10-YL COMP Vmio et ai in Chem. Abstr. Vol. 71, Col 1] 2976v [72] Inventors: Michele Mastursl, Naples; Sabino (1969) Lembo, Pouuoli; Rene Viterbo, Na- P E dfifi LQD D pies, all of Italy Attorney-Eugene 0. Retter and George W. Ruchfuss, [73] Assignee: Richardson-Metre" S.p.A., Naples,

Italy [57] ABSTRACT [22] Filed: Nov. 17, 1970 New compounds hayin g the following general formula: 21 Appl. No.: 90,488 E, Related US. Application Data [63] Continuation-impart of Ser. No. 715,535,

March 25, 1968, Pat. No. 3,600,391. N

' R [30] Foreign Application Priority Data March 28, 1967Italy ..35729 A/67 X in which X is O, or S; and R, and R are a 521 US. Cl ..260/268TR variety of substitutents- The compounds have useful 51 Int. Cl. ..C08d 51/70 pharmacological activities which include hypertensive, 58 Field of Search ..260/268 TR sedative, m l r l x n local anesthetic, analgesic, v s anti-pyretic, and anti-inflammatory activities. Various [56] References Cited salts of these compounds are also useful and are included within the scope of the present invention. UNITED STATES PATENTS Processes of preparing these compounds are described.

3,600,391 8/1971 Mastursi et a1. ..260/268 TR 12 Claims, N0 Drawings DIBENZO(B,F)OXEPIN-AND COMPOUNDS This application is a continuation-in-part of applicants copending application Ser. No. 715,535, filed Mar. 25, 1968 and now U.S. Pat. No. 3,600,391, issued Aug. 17,1971.

This invention relates to new and useful en-arnines characterized by having the following general formula:

in which X isi), or=S; R is hydrogen, halogen, lower alkoxy, lower alkyl, amino, nitro, monoalkylamino, dialkylamino, trifluoromethyl, sulfonyl, or sulfonylamide; and R is hydrogen, lower alkyl, phenyl, phenethyl, benzyl, benzoyl, carbalkoxy, carbalkoxyalkyl, phenacyl, alkylacetamide, dialkylacetamide, alkylcarboxamide, phenylcarboxarnide, halophenylcarboxamide, phenylthiocarboxamide, cyanoethyl, picolyl, dialkylaminoalkyl, cyclopropylmethyl, allyl, or propargyl.

The acid addition salts of these new compounds as well as the oxonium, and sulfonium, and the sulfoxides and sulfones of those having a sulfur atom are included within the scope of the present invention.

En-amines are peculiar compounds and are, therefore, considered as a separate class of nitrogen-containing compounds and not as simple amine derivatives. Detailed reviews are devoted to en-amines [see for instance Szmuszkowicz, 1., Enamines, pages 1 to 110 in: Raphael, R.A., Taylor, E.C., and Wynberg, H., Advances in Organic Chemistry: Methods and Results, Volume 4, lnterscience Publishers, New York (1963)] in which structure as well as reactivity of these compounds are described.

En-amines such as those of the present invention easily undergo hydrolytic cleavage in acidic medium resulting in formation of a keto compound and the split-off amine grouping. However, some of these ketones are devoid of pharmacological activity from which it would appear that the compounds are not metabolized in vivo to the ketone but are transformed in some other way. Another peculiar property of enamines is the ease with which they can be alkylated or acylated. Such alkylation and acylation could be a preliminary step in the metabolic fate of the compounds of the present invention.

The new compounds of the present invention are useful primarily because of their pharmacological ac tivities which include anti-hypertensive, sedative, muscle relaxant, local anesthetic, analgesic, antipyretic, and anti-inflammatory activities as will be more specifically pointed out below.

The most pertinent prior art known to applicants is the publication by W. Tochtermann et al., Ber. 97, 1318 (1964). The Tochtermann et al. publication describes the synthesis of piperidine but not piperazine derivatives, however. Belgian Pat. No. 678,483 issued recently to Rhone-Poulenc on dibenzocycloheptatriene derivatives describes certain en-amines which, however, are carbocyclic and do not have oxygen or sulfur atoms as represented by X in the formula above. It is obvious from theoretical considerations as well as observed pharmacological properties that the presence of a hetero atom in the three ring structure changes the geometric shape of the molecule and the reactivity of the same. It is also known that oxygen and sulfur atoms can form oxonium, sulfonium, and other salts and may be expected to be pharrnacologically difierent in their activities from those compounds having no hetero oxygen or sulfur atoms.

The new compounds of the present invention may be prepared by the method of Tochtermann et al.

(Method A) or by treating the desired IO-keto derivative with a desired piper-azine in a water non-miscible aprotic solvent or in an excess of the organic cyclic nitrogen base (Method B). In addition, the piperazine derivatives may be alkylated, arylated, or acylated to form further derivatives (Method C).

More particularly, Method A is carried out as follows: To a solution of potassium tertiary butylate prepared in situ from potassium and anhydrous tertiary butyl alcohol or the equivalent amount of a suitable base, such as sodium amide, potassium or sodium alcoholate or a tertiary organic base, such as triethylarnine, alkylpiperidine or a base of the anionic ion exchange type dissolved or suspended in a sufficient amount of anhydrous ethyl ether or other nonpolar solvent, such as dioxane, aromatic, alicyclic or aliphatic hydrocarbon, such as benzene, toluene, cyclohexane, hexane or pentane, is added a solution in a non-polar solvent of the desired unsaturated halogen derivative (chloro or bromo derivative) of the formula:

To this solution is added the solution of a desired piperazine base dissolved in the suitable non-polar anhydrous solvent, such as ethyl ether, dioxane, aromatic, alicyclic or aliphatic hydrocarbon.

The molar ratio between the base, halogen derivative, and piperazine base can be considerably varied depending on the reactivity of the various compounds involved in-the reaction, as can be seen from the examples. The above mixture is allowed to react at a temperature between room temperature and boiling point of the solvent in a period of time between three and 24 hours. The reaction mixture is then partitioned in the usual manner between water and a water-immiscible organic solvent, such as ethyl ether, toluene, benzene, or ethyl acetate, chloroform or other. The organic layer is evaporated and the residue is crystallized from a suitable solvent, such as ethyl acetate, ethanol, methanol, or other, yielding the pure reaction product.

The process of Method B is carried out as follows: An enolizable keto derivative of the formula:

together with the piperazine base is dissolved in a suitable amount of anhydrous benzene or toluene or other, with water non-miscible, aprotic solvent or in an excess of the piperazine base and refluxed with the simultaneous elimination of the water formed during the reaction for a period of time between 24 and 100 hours in the presence of a Lewis acid such as p-toluenesulfonic acid, or the salt of a strong mineral acid with a weak organic base such as piperazine hydrochloride or other. After the end of the reaction, the solution is partitioned between water and a water insoluble solvent, such as ethyl ether, ethyl acetate, benzene, toluene, chloroform, or other. The organic phase is concentrated and the residue is crystallized from a suitable solvent, such as methanol, ethanol, ethyl acetate or other yielding the pure crystalline compound.

Further derivatives are prepared by Method C as follows: To the N-substituted piperazine derivative, wherein R is hydrogen, prepared as described above dissolved in an anhydrous aprotic solvent, such as benzene, toluene, or other aromatic or aliphatic hydrocarbon or ethyl ether, is added the alkylating, arylating, or acylating agent if necessary in the presence of a suitable base, such as anhydrous sodium carbonate or bicarbonate, or other basic alkali metal salt or alcoholate or organic tertiary nitrogen base, such as pyridine, alkyl-piperidine, triethylarnine or anionic ion exchange resin. The reaction temperature can be chosen in the range from C. to boiling temperature of the solvent and the reaction time is between one hour and 24 hours, depending on the reactivity of the compounds involved in the reaction. The reaction mixture is extracted with a water non-miscible solvent, such as ethyl ether, ethyl acetate, benzene, toluene, chloroform or other. The organic layer is concentrated and the residue crystallized from a suitable solvent, such as benzene, methanol, or ethylacetate.

The invention will now be illustrated by examples showing the preparation of a number of the compounds,

of the present invention by means of the several methods mentioned above.

EXAMPLE 1 N-[ Dibenzo( b,f) oxepin- 1 O-yl ]-N -methylpiperazine 29 grams (138 mmol) Dibenzo(b,f)oxepin-l0(l1H)- one Known compound: See Shoshichiro Kimoto et al. J. Pharm. Soc. Japan 74, 426 (1954) CA. 49, 5374b (1955),

29 grams (290 mmol) N-methylpiperazine, and

0.5 gram p-toluenesulfonic acid monohydrate were dissolved in 100 milliliters of anhydrous toluene. The solution was refluxed for 71 hours, and the formed water was separated with a Dean-Stark trap. The solution was colled and partitioned between toluene and water. The organic layer was washed with water until neutral, dried over anhydrous Na SO and distilled under vacuum (water jet pump). The solid brown residue (46.6 grams) was crystallized from petroleum ether 60 to 80 C. and had a melting point of 11 1 to 1 12 C.

UV. in ethanol percent Amax=3l2mp4 e= 10,600

To a solution of four grams of maleic acid dissolved in 30 milliliters of boiling ethanol is added a solution of 10 grams of N-[dibenzo(b,f)oxepin-10 yl]-N-methylpiperazine in 50 milliliters of boiling ethanol. The hot solution was filtered and slowly added to 350 cc anhydrous ethyl ether and kept at 4 C. for four hours. The filtered precipitate was washed four times with 10 milliliters anhydrous ether and dried at room temperature at a pressure of 0.01 mm Hg. The obtained maleate acid addition salt in the form of white crystals had a melting point of 195 to 196 C. Yield: 13.2

ams.

U.V. in ethanol 95 percent A max=308 mp; e= 10,300

This compound exhibited muscle relaxing, hypotensive activity, and reduced spontaneous motility in mice by the method of Dews as illustrated in the tables which follow the specific examples. Similarly, the pharmacological activities of various other compounds of the specific examples are shown in these tables.

EXAMPLE II N-[ 8-Chloro-dibenzo(b,f)oxepinl 0yl]-N'- methylpiperazine 17.5 8-Chloro-dibenzo(b,f)oxepin-l010( 1lH)-one (71.5 mrnol)( Known compound: See J. R. Geigy. A.-G. Neth. Patent 6508284 CA. 64, l9574b (1966),

18 grams N-methylpiperazine 180 mmol), and

2.5 grams p-toluenesulfonic acid monohydrate were dissolved in milliliters of anhydrous toluene.

The solution was refluxed for 73 hours, separating off the water with a Dean-Stark trap. The cooled solution was partitioned between toluene and water. The organic phase was washed with water until neutral, dried over anhydrous Na SO and distilled under reduced pressure. The residue was crystallized from ethyl acetate yielding nine grams of white crystals with a melting point of 125 to 128 C.

U.\/. in ethanol 95 percent The above-described compound (8.2 grams) was dissolved in 20 milliliters of boiling ethanol, and 2.9 grams of maleic acid dissolved in 10 milliliters of boiling ethanol were added. Ethyl ether was added to the solution until incipient crystallization (about 300 milliliters). The mixture was kept at 4 C. for four hours and then filtered. The residue was washed four times with 10 milliliters of anhydrous ethyl ether and dried under high vacuum, yielding 7.7 grams of white crystals of the maleate addition salt with a melting point of 1 84 to 1 87 C. (decomposition).

U.V. in ethanol 95 percent EXAMPLE Ill N-[ 8-Methoxy-dibenzo(b,f)oxepin- 1 O-yl] -N' methylpiperazine 10.4 grams (43 mmol) 8-Methoxy-dibenzo(b,f)oxepin-l0(1 ll-l)-one, 10.5 grams mmol) N-methylpiperazine, and

1.2 grams p-toluenesulfonic acid monohydrate were dissolved in 100 milliliters of anhydrous toluene.

The solution was refluxed for 72 hours, separating the formed water with a Dean-Stark trap. The cooled solution was partitioned between toluene and water. The organic phase was washed with water until neutral, and then extracted with an 0.1 N aqueous solution of maleic acid. The aqueous phase was made alkaline with a saturated Nal-lCO solution and extracted with ethyl ether. The organic phase was washed with water until neutral, dried over anhydrous Na SO and then distilled. The residue (nine grants) was crystallized from methyl alcohol to yield nine grams of white crystals having a melting point of 141 to 143 C.

U.V. in ethanol 95 percent N-[ 8-Methoxy-dibenzo( b,f)oxepinl O-yl] -N'- methyl-piperazine (3.8 grams) as prepared above was dissolved in 15 milliliters of boiling ethanol; then 1.3 grams of maleic acid dissolved in five milliliters of boiling ethanol were added. Anhydrous ethyl ether was added to the solution until incipient crystallization (about 150 cc). After four hours at 4 C., the precipitate was filtered ofi, washed four times with five milliliters of anhydrous ethyl ether, dried under high vacuum yielding 3.5 grams of white crystals of the maleate salt with a melting point of 199 C. (decomposition).

U.V. in ethanol 95 percent A max= 300 mu; e= 12,500

EXAMPLE 1V N-[Dibenzo(b,f)oxepinl0-yl]-N-ethylpiperazine 22 grams (104 mmol) Dibenzo(b,f)oxepin-l0( 1 1H)- one,

22 grams (192 mmol) N-ethylpiperazine, and

0.5 gram p-toluenesulfonic acid monohydrate were dissolved in 100 milliliters of anhydrous toluene.

The solution was refluxed for 66 hours; the formed water was separated oil with a Dean-Stark trap. The cooled solution was partitioned between water and toluene. The organic phase was washed with water and toluene. The organic phase was washed with water until neutral; then extracted with 0.1 N aqueous solution of maleic acid. The acid solution was made alkaline with a saturated solution of Nal-lCO and then re-extracted in ethyl ether.

The organic phase was washed with water until neutral, dried over anhydrous Na SO.,, and then distilled. The residue was crystallized from ethyl alcohol. Yield was 7.9 grams with a melting point of 1 13 to 1 15 C. (white crystals).

U.V. in ethanol 95 percent N- Dibenzo( b,f)oxepinl0-yl ]-N'-ethylpiperazine (7.54 grams) was dissolved in 35 milliliters of boiling ethanol and 2.85 grams of maleic acid dissolved in 15 milliliters of boiling ethanol were added. The mixture was kept at 4 C. for 4 hours and then filtered. The precipitate was washed four times with milliliters anhydrous ethyl ether and dried under high vacuum. Yield of maleate salt was 8.4 grams with a melting point 6 of 180 C. (decomposition).

U.V. in ethanol 95 percent A max= 308 mu; e= 10,100

EXAMPLE V N-[Dibenzo(b,f)oxepin- 10-yl]-N'-n-propylpiperazine 22 grams (104 mmol) Dibenzo(b,f)oxepin-10( 1 1H)- one,

22 grams 172 mmol) N-n-propylpiperazine, and

0.6 gram p-toluenesulfonic acid monohydrate were dissolved in 100 milliliters of anhydrous toluene.

The solution was refluxed for hours, separating off the water with a Dean-Stark trap. The cooled solution was partitioned between water and toluene. The organic phase was washed with water until neutral; the base was extracted with an 0.1 N maleic acid solution. The aqueous acid solution was made alkaline with a saturated NaHCO solution and re-extracted with ether. The organic phase was washed with water until neutral, dried over anhydrous Na SO and the solvent distilled ofi. The dark residue was crystallized from ethanol yielding 12.5 grams of white crystals with a melting point of 88 to 90 C.

U.V. in ethanol percent N- Dibenzo( b,f)oxepinl O-yl -N' -n-propylpiperazine (11.8 grams) was dissolved in 60 milliliters of boiling ethanol and to this was added a solution of 3.81 grams of maleic acid dissolved in 25 milliliters of ethanol. Ethyl ether was added until incipient crystallization, and the mixture was allowed to stand at 4 C. for five hours. The precipitate was filtered off, and washed four times with 10 milliliters of ether. It was dried under high vacuum yielding 11.8 grams of compound with a melting point of 188 to 191 C. (white crystals).

U. V. in ethanol 95 percent Amax=308 mp.;e= 10,100

EXAWLE V1 N-[Dibenzo(b,f)oxepinlO-yl]-N-n-butylpiperazine 22 grams (104 mmol) Dibenzo(b,f)oxepin-l0( 1 111)- one, 22 grams 155 mmol) N-n-butylpiperazine, and 0.6 gram p-toluenesulfonic acid monohydrate were dissolved in ml anhydrous toluene. I

The solution was refluxed for 72 hours, and the formed water separated ofi with a Dean-Stark trap. The cooled solution was partitioned between water and toluene. The organic phase was washed with water until neutral, and then extracted with an 0.1 N aqueous solution of maleic acid. The separated aqueous solution was made alkaline with a saturated solution of NaHCO and re-extracted with ethyl ether. The organic phase was washed with water until neutral, dried over anhydrous Na SO and distilled. The brown residue (18 grams) was crystallized from ethyl alcohol and had a melting point of 8 1 to 83 C. (white crystals).

U.V. in ethanol 95 percent Amax=3l2 mu; 6 10,700

N-[Dibenzo(b,f)oxepin-10-yl]-N'-n-butylpiperazine (9.66 grams) was dissolved in 45 milliliters of boiling ethanol to which was added 3.35 grams of maleic acid dissolved in 25 milliliters of boiling ethanol. The mixture was kept four hours at 4 C. and then filtered. The precipitate was washed four times with 10 milliliters of anhydrous ethyl ether; then dried under high vacuum yielding 9.4 grams of white crystals with a melting point of 1 85 to 187 C. (decomposition).

U.V. in ethanol 95 percent A max 308 mu; e= 10,200

EXAMPLE Vll N-[Dibenzo(b,f)oxepinl -yl ]-N- carbethoxypiperazine 22 grams (104 mmol) Dibenzo(b,f)oxepin-( 1 1H)- one,

22 grarns (138 mmol) N-carbethoxypiperazine, and

0.6 gram p-toluenesulfonic acid monohydrate are dissolved in 100 ml anhydrous toluene.

The solution was refluxed for 74 hours, separating oh the water with a Dean-Stark trap. The cooled solution was partitioned between water and toluene. The organic phase was washed with water until neutral, dried over anhydrous Na SO and the solvent distilled off. The residue was crystallized from methanol yielding 16 grams of white crystals with a melting point of ll4to 116C.

U.V. in ethanol 95 percent A max= 309 mu; e= 10,350

EXAMPLE V111 N-[ Dibenzo(b,f)oxepin- 10]-N'-phenylpiperazine 22 grams 104 mmol) Dibenzo(b,f)oxepin-l0( 1 1H)- one,

22 grams (135 mmol) N-phenylpiperazine, and

0.6 gram p-toluenesulfonic acid monohydrate were dissolved in 100 ml anhydrous toluene.

The solution was refluxed for 64 hours, separating off the water with a Dean-Stark trap. The cooled solution was partitioned between toluene and water. The organic phase was washed with water until neutral, dried over anhydrous Na SO and distilled under reduced pressure. The residue was crystallized from ethyl acetate yielding 13 grams of white crystals with a melting point of 148 to 150 C.

U.V. in ethanol 95 percent A max 308 mp; e 10,700

EXAMPLE IX N-[ Dibenzo( b,f)oxepin- 10-yl]-N'-benzylpiperazine 18 grams Dibenzo(b,f)oxepin-l0(l1H)-one (85.6

mmol),

18 grams N-benzylpiperazine 100.2 mmol and 0.5 gram p-toluenesulfonic acid monohydrate were dissolved in 100 ml anhydrous toluene.

The solution was refluxed for 100 hours, separating off the water with a Dean-Stark trap. The cooled solution was partitioned between water and toluene. The organic layer was washed with water until neutral, dried over anhydrous Na SO and the solvent evaporated at mm Hg. The brown residue was crystallized from CHCl -ethanol obtaining 24.8 grams of white crystals with a melting point of 159 to 160 C.

U.V. in ethanol 95 percent Amax=3l2m;t; e= 10,400

EXAMPLE X N-[ Dibenzo( b,f)thiepinl0-yl ]-N'-methylpiperazine A mixture of 15 grams (66 mmol) dibenzo(b,f)thiepin-l0( 1 1H)- one J. O. Jilek et 31., 96, 182, (1965), 30 grams (300 mmol) N-methylpiperazine, and 6 grams (34 mmol) N-methylpiperazine dihydrochloride was slightly refluxed for 48 hours. The excess N- methylpiperazine (about 10 cc) which contained the water formed during the reaction was distilled 0E. The cooled residue was partitioned between ethyl ether and a saturated solution of NaHCO The organic phase was extracted two times with a saturated solution of Nal-l- CQ, and then with water until neutral. The organic phase was extracted with an 0.1 N aqueous solution of maleic acid. The acid solution was made alkaline with a saturated solution of Nal-lCO and then extracted in ethyl ether. This organic phase was washed with water until neutral, dried over anhydrous Na SO and then distilled. The residue was crystallized from petroleum ether 60 to C. yielding 10.4 grams of compound with a melting pointof l 15to 117C.

U.V. in ethanol percent A max= 268 mu; e= 10,900

To 7.9 grams of N-[dibenzo(b,f)thiepinlO-yl]-N- methylpiperazine dissolved in 25 cc of boiling ethanol were added 2.97 grams of maleic acid dissolved in 10 cc of boiling ethanol. It was kept at 4 C. for four hours and then filtered. The precipitate was washed four times with 10 cc of anhydrous ethyl ether and dried under high vacuum. Yield of compound was 10 grams with a melting point of 2 13 C. (decomposition).

U.V. in ethanol 95 percent A max=265 m,rt;e= 11,850

Amax=301 mu; e=7,950

EXAMPLE XI N-[ Dibenzo(b,f)thiepin- 1 O-yl}-N'-n-propylpiperazine A mixture of 22 grams (97.2 mrnol) 10(1 1H)one, 34 grams (245 mmol) N-n-propylpiperazine, and 16 grams (79.5 mmol) N-npropylpiperazine dihydrochloride was slightly refluxed for 64 hours. The excess N-npropyl-piperazine (about 15 cc) which contained water formed during the reaction was distilled off. The cooled residue was partitioned between ethyl ether and a saturated solution of Nal-lCO The organic phase was washed two times with a saturated solution of Nal-ICO and then with water until neutral. It was then extracted with an 0.1 N aqueous solution of maleic acid. The acid solution was made alkaline with NaI-lCO (saturated solution) and extracted in ethyl ether. The organic phase was washed with water until neutral, dried over anhydrous Na SO and distilled. The oil residue was dibenzo(b,f)thiepinchromatographed over neutral, activated A1 (Activity Brockman I). The petroleum ether (boiling point 40 to 70 C.) benzene (1:1) eluate was crystallized from petroleum ether (boiling point 40 to 70 C.) yielding 9.0 grams of compound in the form of white crystals with a melting point of 80 to 82 C.

U.V. in ethanol 95 percent max=268 mp; e= 10,400

A max= 308 my; e= 8,000

To 8.71 grams of the N-[dibenzo(b,f)thiepin-l0-yl]- N'-n-propylpiperazine, prepared as described above, dissolved in 40 cc of boiling ethanol were added 3.00 grams of maleic acid dissolved in 10 cc of boiling ethanol. The formed salt was allowed to crystallize and was then filtered off. The precipitate was washed four times with 10 cc anhydrous ethyl ether, and then dried. White crystals (8.7 grams) with a melting point of 171 to 173 C. (decomposition) were obtained.

U.V. in ethanol 95 percent A max= 265 mp; e= 12,400 A max= 302 mp; e= 8,300

EXAMPLE XII N-[Dibenzo(b,f)thiepin-10-yl]-N'-isopropylpiperazine A mixture of 20 grams (88 mmol) dibenzo(b,f)thiepin-l0(11I-I)- one, 27.7 grams (216 mmol) N-iso-propylpiperazine, and 7 grams (34 mmol) N-iso-propylpiperazine dihydrochloride was kept slightly boiling for 50 hours. The excess N-isopropyl-piperazine (about 10 cc) which contained water formed during the reaction was distilled off. The cooled residue was partitioned between ethyl ether and a saturated solution of NaI-ICO The organic phase was washed two times with a saturated solution of NaHCO and then washed with water until neutral. The organic phase was extracted with an 0.1 N aqueous solution of maleic acid. The acid solution was made alkaline with a saturated solution of NaHCO and extracted in ethyl ether. The organic phase was washed with water until neutral, dried over anhydrous Na SO and distilled. The yield of compound was 3.2 grams with a melting point of 82 to 86 C. It was chromatographed over neutral, activated Al O (Activity Brockman I); 2.27 grams were eluted with petroleum ether (boiling point 40 to 70 C.) benzene (lzl) and crystallized from ethyl acetate; melting point was 83 to 85 C. (white crystals).

U.V. in ethanol 95 percent )1 max 268 my; 6 10,400

A max= 308 mp; e= 8,000

To 0.685 gram of N-[dibenzo(b,f)thiepin-10-yl]-N'- iso-propylpiperazine dissolved in 3 cc boiling ethanol were added 0.236 gram maleic acid dissolved in 1.5 cc boiling ethanol. The formed salt was allowed to crystallize and was then filtered off. The precipitate was washed four times with 3 cc anhydrous ethyl ether and dried. It yielded 0.83 gram of compound in the form of white crystals with a melting point of 196 to 199 C.

U.V. in ethanol 95 percent It max= 265 mu; 6 12,200 A max= 303 ,u; e= 8,200

EXAMPLE XIII N- Dibenzo( b,f)thiepinl O-yl ]-N'-iso-butylpiperazine A mixture of 20 grams (88 rmnol) dibenzo(b,f)thiepin-10(11H)- one, 36 grams (253 mmol) N-iso-butylpiperazine, and 13 grams (60.4 mmol) N-iso-butylpiperazine dihydrochloride was gently boiled for 48 hours. Successively, 10 cc of N-iso-butylpiperazine which contained water formed during the reaction were distilled oil. The cooled residue was partitioned between ethyl ether and a saturated solution of Nal-lCO The organic phase was washed two times with a saturated solution of NaI-ICO in water until neutral and then extracted with an 0.1 N solution of maleic acid. The acid solution was made a1- kaline with a saturated solution of NaHCO and was extracted in ethyl ether. The organic phase was washed with water until neutral, dried over anhydrous Na SO and distilled. The residue was crystallized from ethyl acetate yielding 10.2 grams of compound with a melting point of 94 to 96 C.

U. V. in ethanol 95 percent ltmax=268 m;1.;e= 10,300

Amax=308 mu; e= 8,000

To 9.84 grams of N-[dibenzo(b,f)thiepin-l0-y1]-N'- iso-butylpiperazine dissolved in 30 cc boiling ethanol were added 3.25 grams of maleic acid dissolved in 10 cc of boiling ethanol. It was kept at 4 C. for four hours and then filtered. The precipitate was washed four times with 10 cc of anhydrous ethyl ether and dried under high vacuum. Yield of the compound in the form of white crystals was 12 grams with a melting point of 195 to 197 C. (decomposition).

U.V. in ethanol 95 percent Amax=265 my; e= 1 1,650

A max 303 mu; 6 8,000

EXAMPLE XIV N-[ Dibenzo(b,f)thiepinl 0-yl]-N-benzylpiperazine A mixture of 15 grams (66 mmol) dibenzo(b,f)thiepin-l0(l1H)- one, 49.7 grams (282 mmol) N-benzylpiperazine, and 8.2 grams (33 mmol) N-benzylpiperazine dihydrochloride was slightly refluxed for 48 hours. About 10 cc of N- benzylpiperazine which contained water formed during the reaction were distilled off. The cooled residue was partitioned between ethyl ether and a saturated solution of NaHCO and then washed with water until neutral, dried over anhydrous Na SO and the solvent v distilled. The residue was crystallized from ethyl acetate yielding 1 1.2 grams of compound in the form of white crystals with a melting point of 137 to 139 C.

U.V. in ethanol percent A max 267 m e 10,600 kmax=305 mu; e= 8,150

EXAMPLE XV N-[Dibenzo( b,f)thiepinl 0-yl ]-N- carbethoxypiperazine Amixture of 22 grams (97.2 mmol) dibenzo(b,f)thiepin- 10(1 1H)-one, 29.3 grams (184.3 mmol) N-carbethoxypiperazine,

and

EXAMPLE XVI N-[ 8-Methyl-dibenzo(b,f)thiepinl -yl]-N- benzylpiperazine A mixture of 12.4 grams 1 mmol) 8-methyldibenzo(l:a,f)thiepin-(lll-l)-one J. R. Geigy A.-G. Netherlands Patent 6,404,862 CA. 62,

30 grams (170 mmol) N-benzylpiperazine, and

7 grams (28 mmol) N-benzylpiperazine dihydrochloride was slightly refluxed for 48 hours. The water formed during the reaction was distilled off, collecting about 5 cc of distillate. The cooled residue was partitioned between ethyl ether and a saturated solution of NaH- CO The organic phase was washed two times with a saturated solution of NaHCO washed with water until neutral, and then extracted with an 0.1 N aqueous solution of maleic acid. The acid solution was made alkaline with a saturated solution of NaHCO and extracted in ethyl acetate. This organic solution was washed with water until neutral, dried over Na SO and then distilled. The oily residue was crystallized from CHCl -MeOl-l (1:9) yielding 10.2 grams of the compound in the form of white crystals with a melting point of 128 to 131 C.

U.V. in ethanol 95 percent Amax=264 mu;e= 11,200

llmax=308 mp1.;e=8,600

EXAMPLE XVII N[ 8-Fluoro-dibenzo(b,f)oxepinl O-yl ]-N- methylpiperazine A solution of grams (87 mmol) 8-fluoro-dibenzo(b,f)oxepin- 10( l lH)-one, grams (240 mmol) N-methylpiperazine, and 7 grams p-toluenesulfonic acid monohydrate were dissolved in 150 ml anhydrous toluene and refluxed for 70 hours, separating the formed water with a Dean-Stark trap. The cooled solution was partitioned between toluene and water. The organic phase was washed with water until neutral and then extracted with an 0.1 N aqueous solution of maleic acid. The aqueous phase was made alkaline with a saturated NaHCO solution and extracted with ethyl ether. The organic phase was washed with water until neutral, dried over anhydrous Na SO and distilled. The residue (20 grams) was crystallized from ethyl acetate and had a melting point of 135 to 138 C.

U.V. in ethanol percent Amax=295 mu; e=9,l50

To 12.32 grams (39.6 mmol) of N-[8-fluorodibenzo(b,f)-oxepin-10-yl]-N'-methylpiperazine dissolved in 50 milliliters of boiling ethanol were added 4.6 grams (39.6 mmol) maleic acid dissolved in 15 milliliters of boiling ethanol. It was allowed to stand for four hours at 4 C. The white crystals obtained were filtered off and washed with ethyl ether. Yield was 10.2 grams with a melting point of 172 C. (decomposition).

U.V. in ethanol 95 percent A max=293 mp; e=9,450

EXAMPLE XVIII N-[ Dibenzo( b,f)thiepin-5 ,S-dioxidel 0-yl -N- methylpiperazine To a solution of 7.14 grams (63.6 mmol) potassium tertiary butoxide in 150 milliliters of anhydrous tertiary butyl alcohol and 300 milliliters of anhydrous ethyl ether were added 62 grams (620 mmol) of N-methylpiperazine and 20 grams (62.2 mmol) l0-bromodibenzo(b,f)thiepin-5,5-dioxide( This compound has been prepared following the procedure described by W. Tochtermann, Knut Oppenlander und Michel Nguyen-Duong Hoang: Liebigs Ann. Chem. 701, 117 (1967). The solution was stirred 20 hours. it was poured into water and extracted with ethyl acetate. The organic phase was washed with water until neutral, and then extracted with an aqueous solution of 0.1 N maleic acid. The separated acidic solution was made alkaline with a saturated NaHCO solution and extracted with ethyl acetate. The organic phase was washed with water until neutral, dried over anhydrous Na SO and then distilled. The white crystalline residue was crystallized from 1,2-dichloroethane-ethyl acetate yielding 13 grams of compound with a melting point of 193 to 196 C.

U.V. in ethanol 95 percent ltmax=227 mu; e=37,400

A max=322 mu; 6 1 1,850

EXAMPLE XIX N- Dibenzo( b,f) thiepinl 0-yl] -piperazine A mixture of 5 grams (22.1 mmol) dibenzo(b,f)thiepin-l0(l 1H)- one, 7 grams (81.3 mmol) piperazine, and 2.1 grams ptoluenesulfonic acid monohydrate in ml anhydrous xylene was slightly refluxed for 28 hours. The solvent was distilled, and the cooled residue was partitioned between ethyl acetate and a saturated solution of Nal-l- CO;,. The organic phase was washed with water until neutral, dried over anhydrous Na SO and then distilled. The oily residue (6 grams) was chromatographed over neutral, activated A1 0 (Activity Brockman l). The substance eluted with the benzeneethyl ether (1:1) mixture (5.7 grams) was crystallized from ethyl ether and had a melting point of 134 C. (decomposition).

U.V. in ethanol 95 percent Amax=267 mu; e= 10,000

A max=307 mu; e=7,700

EXAMPLE XX EXAMPLE XXI N-[ 8-Pluoro-dibenzo(b,f)oxepinl -yl]-N- benzylpiperazine A solution of 20 g of 8-fluoro-dibenzo(b,f)oxepinl0( 1 1H)- one, 40 g of N-benzylpiperazine and 6.5 of ptoluenesulfonic acid in 120 ml of toluene was refluxed 70 hours, separating off the water with a Dean-Stark trap. The cooled solution was extracted with a saturated NaI-ICO solution, washed with water and dried over anhydrous Na SO Evaporation of the solvent yielded 25 g of residue which was crystallized from ethylacetate and had a melting point of 137- 1 39 C.

U.V. in ethanol 95 percent A max=297 mp; e=8,800 Amax=3l6my.;e=8,950

EXAMPLE XXII N-[ 8-Fluoro-dibenzo(b,f)oxepinl O-yl ]-N'- carbethoxypiperazine A solution of 20 g of 8-fluoro-dibenzo(b,f)oxepin- 10(1 1H)- one, 27 g of N-carbethoxypiperazine and 6 g of p-toluenesul-fonic acid in 120 ml of toluene was refluxed 70 hours, separating off the water with a Dean-Stark trap. The cooled solution was extracted with a saturated NaHCO solution, washed with water and dried over anhydrous Na SO Evaporation of the solvent and crystallization of the residue from ethylacetate gave 9.3 g of compound with a melting point of 120-12lC.

U.V. in ethanol 95 percent EXAMPLE XXIII N-[ 8-Fluoro-dibenzo(b,f)oxepinl O-yl -piperazine A solution of 20 g of 8-fluoro-dibenzo(b,f)oxepin- 10(1lI-1)- one, 30 g of piperazine and 8.5 g of ptoluenesulfonic acid in 170 ml of toluene was refluxed 48 hours separating off the water with a Dean-Stark trap. The cooled mixture was extracted with a saturated NaHCQ, solution, washed with water and dried over anhydrous Na SO Evaporation of the solvent yielded 25 g of residue which was crystallized from ethanol and had a melting point of l l9-12l C.

UN. in ethanol percent A max= 296 mu; e= 8,800

A max=3l5 mu; e=8,970

EXAMPLE XXIV N-[ 8-Methoxy-dibenzo( b,f)oxepinl O-yl ]-N'- benzylpiperazine A solution of 20 g of 8-methoxy-dibenzo(b,f)oxepin- 10-( l lH)-one, 29.3 g of N-benzylpiperazine and 6 g of p-toluene-sulfonic acid in ml of toluene was refluxed 48 hours, separating off the water with a Dean-Stark trap. The cooled solution was treated with a saturated NaI-ICQ solution, washed with water and dried over anhydrous Na SO Evaporation of the solvent and crystallization from CHCl -ethanol gave 17.6 g of white crystals with a melting point of l38-l 39 C.

U.V. in ethanol 95 percent Amax=303mme= 11,700

EXAMPLE XXV N-[ 8-Fluoro-dibenzo( b,f)oxepinl O-yl ]-N- phenylpiperazine A solution of 20 g of 8-fluoro-dibenz0(b,f)oxepin- 10- 1 lH)-one, 28.4 g of N-phenylpiperazine and 6 g of p-toluene-sulfonic acid in 120 ml of toluene was refluxed 48 hours, separating off the water with a Dean-Stark trap. The cooled solution was washed with water and dried over anhydrous Na SO Evaporation of the solvent and crystallization of the residue from ethylacetate gave 12.3 g of white crystals with melting point of "l 47-1 48 C.

U.V. in ethanol 95 percent Amax=294mp.;e= 11,200

EXAMPLE XXVI N-[ 8-Fluoro-dibenzo( b,f)oxepinl O-yl ]-N' N,N- dimethylacetamide)-piperazine To a solution of 6.9 g of N-[8-fluoro-dibenzo(b,f)oxepin-l0-yl]-piperazine in 60 ml of anhydrous benzene, 1.48 g of anhydrous Na CO and 3.11 g of N,N- dimethylchloroacetamide were added under stirring. After refluxing 20' hours the solution was cooled, washed with water and dried over anhydrous Na SO Evaporation of the solvent yielded 7.9 g of residue which was crystallized from methanol and had a melting point of 146 148C.

U.V. in ethanol 95 percent Amax=295 mu; e= 18,100

Amax=315 mu; e= 18,300

EXAMPLE XXVll N-[ 8-Chloro-dibenzo( b,f)oxepin- 1 O-y1]-N'- phenylpiperazine A solution of 25 g of 8-chloro-dibenzo(b,f)oxepinlO(l1H)-one, 33.5 g of N-phenylpiperazine and 5 g of p-toluenesulfonic acid in 150 m] of toluene was refluxed 48 hours, separating ofi the water with a Dean-Stark trap. The cooled solution was extracted with a saturated Nal-lCO solution, washed with water and dried over anhydrous Na SO Evaporation of the solvent and crystallization from ethylacetate yielded 21.3 g of white crystals with a melting point of l69-l 7 0 C.

UN. in ethanol 95 percent A max 302 mu; F 9,950

EXAMPLE XXVIII N-[ 8-Chloro-dibenzo( b,f)oxepinl O-yl l-piperazine A mixture of 60 g of 8-chloro-dibenzo(b,f)oxepin- 10(1ll-l)- one, 84.5 g of piperazine, 10 g of ptoluenesulfonic acid, separating off the water with a Dean-Stark trap. The cooled solution was treated with a saturated NaHCO solution, washed with water and dried over anhydrous Na SO Evaporation of the solvent and crystallization of the residue from benzene yielded 58 g of white crystals with a melting point of 180-182C.

U.V. in ethanol 95 percent EXAMPLE XXIX A max= 316 mu; e=8,950

EXAMPLE XXX N-[ 8-Chloro-dibenzo(b,f)oxepin-10-y1]-N'- carbethoxypiperazine A solution of 20 g of 8-chloro-dibenzo(b,f)oxepinlO-(l 1H )-one, 26 g of N-carbethoxypiperazine and 6 g of p-toluene-sulfonic acid in 150 ml of toluene was refluxed 48 hours, separating off the water with a Dean-Stark trap. The cooled solution was treated with a saturated NaHCO solution, washed with water and dried over anhydrous Na SO Evaporation of the sol vent gave 18 g of residue which was crystallized from CHCh-methanol and had a melting point of 125127 C.

U.V. in ethanol 95 percent 16 EXAMPLEXXXI N-[8-Chloro-dibenzo(b,f)oxepin-10-yl]-N'-(2-methy1- benzy1)-piperazine A mixture of 7.4 g of 8-chloro-dibenzo(b,f)oxepin- 10(1lH)-one, 11 g of N-(2-rnethyl-benzyl)-piperazlne and 3 g of p-toluenesulfonic acid in ml of toluene was refluxed 48 hours, separating the water with a Dean-Stark trap. The cooled solution was treated with a saturated NaHCO solution, washed with water and dried over anhydrous Na SO.,. Evaporation of the solvent and crystallization from ethylacetate yielded 3.5 g of compound with a melting point of 142144 C.

U.V. in ethanol 95 percent Amax=3l6mm e==8,500

EXAMPLEXXXII N-[ 8-Chloro-dibenzo( b,f)oxepin- 10-yl]-N'-(4- methoxybenzyD-piperazine A mixture of 14.5 g of N-[8-chloro-dibenzo(b,f)oxepin-lO-yH-piperazine, 2.86 g of Na CO 7.98 g of 4- methoxybenzyl-chloride in ml of benzene was refluxed 20 hours. The cooled mixture was treated with water, washed until neutral with water and dried over anhydrous Na SO The solvent was evaporated. The residue was crystallized from ethylacetate by filtrating off the insoluble matter and 5 g of the product were obtained with a melting point of l201 2 1 C.

UN. in ethanol 95 percent A max= 320 mu; 6 8,900

EXAMPLE XXXlll N-[ 8-chloro-dibenzo(b,f)oxepin-10-yl]-N-( 3- pyridylmethy1)-piperazine A mixture of 12.8 g of N-[8-chloro-dibenzo(b,f)oxepin-lO-yl}-piperazine, 15 g of Na CO and 8.2 g of 3- chloromethyl-pyridine-hydrochloride in 150 ml of benzene and 220 ml of ethanol was refluxed six hours. After cooling, water was added. The organic layer was washed with water until neutral and dried over anhydrous Na SO.,-,. Evaporation of the solvent yielded 13 g of residue which was crystallized from CHCl ethanol and had a melting point of 14O--141 C.

UN. in ethanol 95 percent A max=320nm; e=9,l50

EXAMPLEXXXIV N-[ 8-Chloro-dibenzo( b,f)oxepin- 1 0-yl]-N'- phenylethylpiperazine A mixture of 10 g of N-[8-chloro-dibenzo(b,f)oxepin-l0-yl]-piperazine, 2.3 g of Na CO and 6.6 g of 2- bromoethyl benzene in ml of benzene was refluxed 20 hours. Water was added to the cooled mixture. The organic layer was washed with water and dried over anhydrous Na SO.,. Evaporation of the solvent and crystallization from ethylacetate yielded 7.5 g of white crystals with a melting point of 159-l6 1 C.

U.V. in ethanol 95 percent Arnax=320 mu; e=9,550

17 EXAMPLE XXXV N-[ 8-Chloro-dibenzo( b,f)oxepinl -yl -N-( 2-chlorobenzyl)-piperazine To a refluxing mixture of g of N-[8-chlorodibenzo(b,f)oxepinl0-yl]-piperazine and 2.3 g of Na CO in 150 ml of benzene, 5.8 g of 2-chloro-benzylchloride were added. After refluxing 20 hours the mixture was cooled, water was added, the organic layer was washed with water until neutral and dried over anhydrous Na SO Evaporation of the solvent yielded 12.8 g of residue which was crystallized from ethylacetate and had a melting point of l64-l 67 C.

U.V. in ethanol 95 percent A max= 320 mp; e= 9,550

EXAMPLE XXXVI N-[ 6-Chloro-dibenzo(b,f)oxepinl 0 yl ]-N-methylpiperazine A solution of g of 6-chloro-dibenzo(b,f)oxepin- 10-(1 ll-l)-one (Preparation A, hereinafter), 15 g of N- methylpiperazine and 4 g of p-toluenesulfonic acid in 160 ml of toluene was refluxed 48 hours separating off the water with a Dean-Stark trap. The cooled solution was treated with a saturated NaHCO solution, washed with water and extracted with 0.1 N maleic acid and the acidic layer was made alkaline with 10 percent Na CO and extracted with ethyl ether. The ethereal phase was washed with water and dried over anhydrous Na SO Evaporation of the solvent yielded 10.6 g of residue which was crystallized from ethylacetate and had a melting point of 9799 C.

U.V. in ethanol 95 percent EXAMPLE XXXVII N-[ 6-Chloro-dibenzo( b,f)oxepin- 1 0y] l-piperazine U.V. in ethanol 95 percent A max=3l5 mp; e=9,600

EXAMPLE XXXVHI N-[ 6-Chloro-dibenzo( b,f)oxepinl 0-yl]-N'-( 2- pyridinomethyl)-piperazine To a refluxing mixture of 11 g of N-[6-Chlord U.V. in ethanol percent A max=254 rnp; e= 12,100 Amax=3l5 mu; e=9,750

EXAMPLE XXXIX N-[ 8-Fluoro-dibenzo( b,f)oxepin- 1 O-yl ]-N'-(N-npropyl-2-methyl-acetarnide )-piperazine 2.16 g N-n-propyl-2-chloropropionamide dissolved in 30 ml anhydrous benzene were slowly added to a stirred mixture of 10 grams N-[8-fluorodibenzo(b,f)oxepin-10-yl]piperazine, 1.6 g anhydrous Na CO ml anhydrous benzene. The mixture was refluxed under stirring for 20 hours and then cooled in an ice-bath. Water was added and the benzenic solution was washed with water and dried over anhydrous Na SO The solvent was distilled off under vacuum and the residue was crystallized from ethanol separating ofi the insoluble matter. 5.2 g of compound were obtained with a melting point of l55l56 C.

U.V. in ethanol 95 percent A max=295 mp; e=9,050

EXAMPLE XL 5.61 g N,N-diethyl-2-chloropropionamide dissolved in 60 ml anhydrous benzene were slowly added to a mixture of 15 g N-[8-fluoro-dibenzo(b,f)oxepin-l0-yl]- piperazine, 2.12 g anhydrous Na CO and ml anhydrous benzene. The mixture was refluxed for 20 hours with stirring and then cooled in an ice-bath. Water was added and the mixture was shaken enough. The benzene-layer was washed with water and dried over Na SO The solvent was distilled off under vacuum. The residue was crystallized from ethanol, separating off the insoluble matter. 3.25 g of obtained compound had a melting point of l65166 C.

U.V. in ethanol 95 percent A max= 295 mu; e= 8,850

EXAMPLE XLI 3.05 g N-ethyl-chloroacetamide dissolved in 50 ml anhydrous benzene were slowly added to a boiling mixture of 15 g N-[8-Fluoro-dibenzo(b,f)oxepin-10-yl]- piperazine, 2.12 g anhydrous Na CO and 180 ml anhydrous benzene. The mixture was refluxed for 20 hours with stirring and then cooled in an ice-bath. Water was added and the mixture was shaken enough. The benzene layer was washed with water and dried over anhydrous Na SO The solvent was distilled off under vacuum and the residue crystallized from chloroform-ethanol. The compound (8.9 g) had a melting'point of l90-l9l C. r I

U.V. ethanol 95 percent A max= 295 my; e= 9,050

PREPARATION OF STARTING MATERIALS Preparation A 6-chIoro-dibenzo( b,f)oxepinl l lI-I)-one A mixture of 222 g of 2-(2-chlorophenoxy)-phenylacetic acid in 2200 ml of polyphosphoric acid was stirred, under N three hours at 120 C. The cooled mixture was poured into ice-water and extracted with ethyl ether. The ethereal phase was extracted with percent Na CO washed with water and dried over anhydrous Na SO Evaporation of the solvent yielded 180 g of residue which was distilled and had a boiling point of 168 C. (0.01 mm Hg) and a melting point of 83-84 C. (from methanol).

U.V. in ethanol 95 percent A max= 249 my; a 8,050

)r max= 309 my; 6 2,700

PREPARATION B 2-( 2-Chlorophenoxy)-phenylacetic acid A mixture of 325.5 g of 2-(2chlorophenoxy)- acetophenone, 71.2 g of sulfur and 184 ml of morpholine was refluxed nine hours. The cooled mixture was partitioned between benzene and N HCl. The organic layer was washed with water and dried over anhydrous Na SO Evaporation of the solvent yielded 486 g of residue which was dissolved in 1200 ml of acetic acid, 455 ml of 96 percent I-I SO and 655 ml of water. The solution was refluxed 20 hours. After cooling the solution was poured over ice-water and the precipitate was collected and dissolved in benzene. The solution was extracted with 10 percent Na CO The alkaline solution was acidified with 6N HCl and extracted with ethyl ether. The ethereal phase was washed with water and dried over anhydrous Na SO Evaporation of the solvent yielded 254 g of residue which was crystallized from ethylacetate and had a melting point of 1 14 1 16 C.

U.V. in ethanol 95 percent PREPARATION C 2-(2-Chlorophenoxy)-acetophenone To a solution of 160 g of 85% KOI-I in 800 ml of ethanol, 293 g of o-chlorophenol were added. The solvent was evaporated and to the residue, 293 g of ochlorophenol, 352 g of o-chloroacetophenone and 37.7 g of copper powder were added. The mixture was stirred under N five hours at 150 C. After cooling, the mixture was dissolved in ethyl ether, extracted with 2N NaOH, washed with water and dried over anhydrous Na SO Evaporation of the solvent and distillation of the residue yielded 351 g of compound with boiling point 201 C./20 mm Hg and melting point 43-45 C. (from petroleum ether 4070).

U.V. in ethanol 95 percent A max 240 my; 5 10,400

A max=296 mu; s= 3,300

The pharmacological activity of the several different compounds described above will be shown in the following tables.

TABLE 1 Spontaneous Motility (Mouse) Method: Dews Administration Route: Dose:

per os l/S LD TABLE 2 Hypotensive Activity (Rat) Administration Route:

Dose:

per os us u),

Compound of Example 1 Example III Example IV Example V Example VI Example X Example XI Example XIII Example XXIII Example XXVI Example XXVIII Example XXX Example XXXI Example XXXVI Example XXXVI] Example XXXVIII Example XXXIX TABLE 3 Anti-inflammatory Activity (Rat) Carrageenan oedema Method:

Administration Route: Dose:

Compound of Example 11 Example 111 Example IV Example X Example XI Example XIII Example XV Example XVI Example XXI Example XXII Example XXIII Example XXVI Example XXVII Example XXXIII Example XXXVI Example XXXVII Example XXXVIII TABLE 4 Hypothermia (Rat) Administration Route: Dose:

l/S LD Compound of %Reduction ofPassa s 9 87 -99 78 100 100 Pressure Modification -40 (Cat) -52 21 20 27 96 Reduction ofOeclema 62 57 59 58 73 Mod. Body Temp.

2 1 22 E l n 3 68* (time) mide, (lower)alkylcarboxamide, phenylcarboxamide, 225 W halophenylcarboxamide, phenylthiocarboxamide, a pl x Hours) cyanoethyl, picolyl, or di(lower)alkylamino(lower)alk 223 v I {:2 (2 yl; and the pharmacologically acceptable acid addition, Exam le xvl L7 3 Hours) 5 oxonium and sulfonium salts thereof.

2. The compound of claim 1 which is N-[8-Chloro- TABLE 5 dibenzo-( b,f)oxepin-l-yl]-N'-methylpiperazine.

3. The compound of claim 1 which is N-[8-Methoxy- Analgesic Activity (Mouse) dibenzo-( b,f)oxepin-l0-yl]-N'-methylpiperazine.

k gg f Rme i ig o 4. The compound of claim 1 which is N-[8-Fluoro- Dose; :7 u) dibenzo-(b,f)oxepin-l0-yll-N'emethylpiperazine.

com um of g l g 5. The compound of claim 1 which is N- Exam gle u gi [Dibenzo(b,f)-oxepin-l0-yl]-N'-methylpiperazine. Example Ill 234 l 5 6. The compound of claim 1 which is N- 22123:: a [Dibenzo(b,f)-thiepinl 0-yl]-N'-methylpiperazine. Example vll +344 7. The compound of claim 1 which is N- 335: :38; [Dibenzo(b,f)-oxepinl O-yl ]-N'-phenylpiperazine. Example ggnl +279 8. The compound of claim 1 which is N- Example v +328 [Dibenzo(b f)-thie in-lO- l]-N-be l i razine.

P 3' y P 1 E218 3%] T 2 9. The compound of claim 1 which is N- +l3 :33 m g giggremnaogbf) thlepln 5,5-dlox1de l0 yl] N methyl Ex 1 5,3312 xxvu 37s 10. A compound of claim 1 having the formula Example XXXll l59 Exam le XXXlll 136 Example XXXVI 374 i Example xxxvll 175 1, Example XXXVlIl 288 J TABLE 6 N Myorelaxing Activity (Mouse) W Administration Route: per os Dose: 1/5 LD R Compound of 5b of Fallen Animals Example I 60 0 Example [I] lOO Example IV 813 $1 100 in which R is hydrogen, halogen, lower alkoxy, lower g pi g alkyl, amino, nitro, mono-lower)alkylamino, eifm fili xln 100 di(lower)alkylamino, or trifluoromethyl; and R is Exam le XXIII 1 hydrogen, lower alkyl, phenyl, benzyl, benzoyl, iifivln carb(lower)alkoxy, carb(lower)alkoxy(lower)-alkyl, Example XXXIll l00 phenacyl, (lower)alkylacetamide, di(lower)alkylacetamide, (lower)alkylcarboxamide, phenylcarboxamide, Example xxxlx 100 halophenylcarboxamide, phenylthiocarboxamide, 3:23:: git gyanoethyl, picolyl, or di(lower)alkylamino(lower)alk we claim: 1 1, A compound of claim 1 having the formula 1. A compound having the formula Hi l R4 N "W U N carb(lower)a1koxy,

in which R is hydrogen, halogen, lower alkoxy, lower alkyl, amino, nitro, mono(lower)alkylarnino, di(lower)alkylamino, or trifluoromethyl; and R, is hydrogen, lower alkyl, phenyl, benzyl, benzoyl, carb(lower)alkoxy, carb(lower)alkoxy(lower)-alkyl, phenacyl, (lower)alkylacetamide, di(lower)alkylacetamide, (lower)a1kylcarboxarnide, phenylcarboxamide,

UNllEI) STA'IES PATEN'I OFFICE t (l E RIIFICAIE (1) F CORRECTION I PAlLNl N0. 5 ,681,'j5 t l IM'H I) August 1, 1972 INVINTOR M Michele Masturs i Sabino Lembo and Rene Vi terbo lt rs certrtred that error appears m the atmve-Jrterrtrtrer't patent and that said Letters Patent Q are hereby corrected as shown below;

Column 5 l ine 62, "col led should read "cooled" Column 4,

line 29, "10lO(llH)" should read "10(11H)". Column 8, line 11, J. 0. J l lek et al 96, 182 1965) should read J. O. J i lek et LM. H. Chem. 96, 182 1965) l ine 67, "The oi l res idue" should read "The oi ly residue". Column 10, l ine 2, "X max 503 u" should read "k max 503 mu. Column 13, l lne 56, and 6.5 of" should read and 6.5 g of". Column 15, line 15, "169-17 0C." should read 169-17OC.". Column 20, l ine 20, Example XXI" should read Example XXXI".

. I Signed and Scaled this eighteenth Day Of November 1975 [SE AL I Arrest:

RUTH C. MASON C. MARSHALL DANN .lI/LSIIHR ()f/Ht' V ('nmmr'sxmm'r Hr Parents and Trademarks 

2. The compound of claim 1 which is N-(8-Chloro-dibenzo-(b, f)oxepin-10-yl)-N''-methylpiperazine.
 3. The compound of claim 1 which is N-(8-Methoxy-dibenzo-(b, f)oxepin-10-yl)-N'' -methylpiperazine.
 4. The compound of claim 1 which is N-(8-Fluoro-dibenzo-(b, f)oxepin-10-yl)-N''-methylpiperazine.
 5. The compound of claim 1 which is N-(Dibenzo(b,f)-oxepin-10-yl)-N''-methylpiperazine.
 6. The compound of claim 1 which is N-(Dibenzo(b,f)-thiepin-10-yl)-N''-methylpiperazine.
 7. The compound of claim 1 which is N-(Dibenzo(b,f)-oxepin-10-yl)-N''-phenylpiperazine.
 8. The compound of claim 1 which is N-(Dibenzo(b,f)-thiepin-10-yl)-N'' -benzylpiperazine.
 9. The compound of claim 1 which is N-(Dibenzo(b,f)-thiepin-5,5-dioxide-10-yl)-N''-methylpiperazine.
 10. A compound of claim 1 having the formula
 11. A compound of claim 1 having the formula
 12. A compound of claim 1 wherein R1 is methyl and R is 8-chloro. 